Hereditary peripheral neuropathies are common human genetic conditions. These clinically and genetically heterogeneous disorders produce progressive deterioration of the peripheral nerves with secondary muscle wasting and weakness in a distal distribution. The application of molecular genetic techniques to this group of disorders has resulted in a more comprehensive understanding of peripheral nerve biology that has important clinical implications. This proposal focuses on the identification of genes, molecular genetic bases, and pathogenic mechanisms regarding the inherited peripheral neuropathy Charcot- Marie-Tooth disease and related disorders. Human genetic and genomic approaches, informatics applications to genome databases, expression profiling coupled with mapping of peripheral nerve- specific genes, comparative genome studies between human and nonhuman primates, and molecular studies of a large cohort of patients manifesting peripheral neuropathies will be utilized to extend our understanding of the human peripheral nerve neurobiology. The major hypotheses to be tested are: (i) the identification of the genes involved in rare forms of familial neuropathy will provide insights into peripheral nerve structure/function and maintenance; (ii) genes that are downstream targets of the transcription factor EGR2 are important candidates for inherited peripheral nerve disease; (iii) structural features of the human genome may result in susceptibility to constitutional DNA rearrangements associated with disease. To address these hypotheses six specific aims are proposed. These include a continuation of the collection of rare neuropathy patients and utilizing DNA samples for such patients to identify additional "peripheral nerve disease genes" by focusing on the genes for proteins that interact with periaxin and genes which are downstream from the peripheral nerve developmental transcription factor EGR2. In addition, a novel general strategy is proposed to identify peripheral nerve- specific genes utilizing bioinformatics procedures and information from the Human Genome Project to establish both positional candidate neuropathy disease genes and a microarray for expression profiling of the peripheral nervous system. Finally, based on some of our previous studies, which have enabled the identification of structural features of the human genome important to the DNA rearrangements responsible for peripheral neuropathy, we will examine additional features which may result in susceptibility to DNA rearrangement as well as examine these genome architectural features during primate species to gain insights into the recent evolution of mammalian genome and its implications for genomic disorders.